Composition Containing Statins and Omega-3 Fatty Acids

ABSTRACT

A combination is described comprising at least one omega-3 fatty acid, optionally esterified or salified, at least one statin, Coenzyme Q10, resveratrol, at least one policosanol, pantethine, selenium, and zinc. This combination is endowed with a synergistic effect and is useful in the treatment of disease forms due to insulin resistance and in cardiovascular diseases.

The present invention relates to a combination of active ingredients andto compositions containing this combination in medical use and in thepreparation of medicaments useful for the treatment of type 2 diabetesand cardiovascular diseases.

Diabetes is a widespread disease throughout the world and is associatedwith major clinical complications involving the microvascular district,such as diabetic retinopathy, diabetic neuropathy and nephropathy, andthe macrovascular district, such as atherosclerosis, peripheralvasculopathies, myocardial infarct and stroke.

Insulin resistance, which characterises type 2 diabetes and its micro-and macrovascular complications is also involved in syndrome X,poly-cystic ovary syndrome, obesity, hypertension, hyperlipidaemias andhypercholesterolaemias (J. Am. Osteopath. Assoc., 2000 October;100(10):621-34; Jama, 2002 Nov., 27;288(20):2579-88).

It is known that hyperlipidaemias, hypercholesterolaemias andhyper-tension play a decisive role in the onset of coronary heartdisease (CHD).

It is also known that an increase in glycosylation of proteins isinvolved in the above-mentioned complications of diabetes (Diabetologia2001 February; 44(2):129-46).

Said complications constitute a serious threat to the life andwell-being of the individual.

Various clinical forms of diabetic disease are known, the most commonbeing type 2 and type 1 diabetes. Type 2 diabetes is characterised byreduced sensitivity to the action of insulin (insulin resistance) andgives rise to an increase in insulin levels in the body in an attempt tocompensate for this deficiency and to a consequent increase in glucoselevels. Numerous reports have confirmed the involvement of insulinresistance in many disease conditions in addition to type 2 diabetesitself, such as dyslipidaemia, obesity, arterial hypertension andcertain macrovascular and microvascular manifestations characteristic ofdiabetic disease itself. The combination of insulin resistance andobesity, hypertension and dyslipidaemia is known as Syndrome X.

Drugs used for many years such as the biguanides and sulphonylurea drugsare available on the market for the treatment of type 2 diabetes. Manyof these, such as, for example, methformin, present gastrointestinaldisorders, danger of acidosis in conditions of renal, cardiac, hepatic,pulmonary insufficiency, etc., as side effects. The sulphonylureas haveepisodes of hypoglycaemia as their possible side effects. Drugs recentlyintroduced onto the market are the thiazolidinediones, whose sideeffects such as liver toxicity, increased LDL cholesterol, weight gainand oedema have given cause for concern.

Hyperlipidaemia is a serious aspect of diabetic disease, constituting,together with the hypertension which is often present, a risk factor foratherosclerosis and for cardiovascular disease which is the primarycause of death in diabetes.

Cardiovascular disease is recognised as the primary cause of death inthe industrialised countries with a high standard of living.

The social cost is enormous, both in terms of disability and invalidityof subjects suffering from it, and in terms of the actual cost of healthfacilities and insurance.

Dyslipidaemia is often associated, also as a consequence, with diabetes.

In WO 02/43659 a combination of statin, docosahexanoic acid, vitamins E,C B6 and B12, folic acid and calcium is described to reduce the riskfactors for cardiovascular disease, such as hypercholesterolaemia andhypertension. In this document there is never any mention of insulinresistance.

Ever increasing attention is being devoted to the so-called risk factorsrecognised as underlying these diseases, and there is still a perceivedneed for a medicament capable of acting on the various sources of thispathological picture, without, at the same time, being associated withsevere side effects, which, as in the case of certain antidiabeticdrugs, may even make it necessary to discontinue the therapy.

SUMMARY OF THE INVENTION

It has now surprisingly been found that a certain combination ofsubstances, known for their specific pharmacological actions, isparticularly indicated for the treatment of insulin resistance, and ofthe pathological aspects related to it, as well as of cardiovasculardiseases. The combination according to the invention comprisesessentially at least one omega-3 fatty acid, optionally esterified orsalified, at least one statin, Coenzyme Q10, resveratrol, at least onepolicosanol, pantethine, selenium and zinc.

The unique combination according to the present invention exerts asurprising effect on insulin resistance, which is not predictable on thebasis of our knowledge of the individual components thereof, and, in anyevent, their combination leads to an unexpected synergistic effect.

The advantage of having such a combination is therefore evident toexperts in the field. It is possible, in fact, to treat insulinresistance, and the pathological forms related to it, particularly asregards the implications of abnormal lipid status, and, at the sametime, the complications or risks affecting the cardiocirculatory system.

The combination according to the present invention can also be used forthe treatment of cardiovascular diseases, without there necessarilybeing any need to treat insulin resistance.

Therefore, one object of the present invention is a combinationcomprising at least one omega-3 fatty acid, optionally esterified orsalified, at least one statin, Coenzyme Q10, resveratrol, at least onepolicosanol, pantethine, selenium, and zinc.

The combination according to the invention can also comprise otheruseful elements, without this substantially impairing the activity.

Another object of the present invention is a pharmaceutical compositioncontaining the above-mentioned combination, optionally in a mixture withone or more pharmaceutically acceptable vehicles or excipients.

The combination according to the present invention can also beformulated as a food supplement, which constitutes a further object ofthe invention.

Other objects of the present invention are various uses of theabove-mentioned combination as a medicament, in particular for thepreparation of a medicament for the treatment of insulin resistance andtype 2 diabetes, with antilipaemic action and a protective action on thecardiovascular system.

In particular, the present invention provides for the use of theabove-mentioned combination for the preparation of a medicament usefulfor the treatment of diseases involving insulin resistance, such as type2 diabetes, Syndrome X, polycystic ovary syndrome, obesity,hypertension, hperlipidaemias and hypercholesterolaemias.

The medicament according to the invention can be used to treat theindividual disease states or to exert a preventive or protective actionagainst them, or to treat a complex pathological picture that includesone or more of the therapeutic aspects seen above. For example, amedicament with a combined action for the treatment of type 2 diabetesand insulin resistance and an antilipaemic and protective action on thecardiovascular system, particularly in certain severe forms of type 2diabetes associated with obesity.

DETAILED DESCRIPTION OF THE INVENTION

The combination according to the present invention consists essentiallyof active ingredients which are known in the medical field and alreadyused in clinical practice. Therefore, they are very easy to procure,inasmuch as they are products which have been on the market for sometime and are of a grade suitable for human or animal administration.

The statins are a known class of drugs used for lowering cholesterollevels. Statins are available on the market or can be prepared accordingto known methods described in the literature.

Any statin is suitable for the purposes of the present invention.Examples of statins are simvastatin, lovastatin, fluvastatin,pravastatin, atorvastatin, cerivastatin and rosuvastatin. Among these,the one preferred is simvastatin.

According to the present invention, it is also possible to combine anumber of statins, depending on their pharmacological characteristicsand on the basis of the common knowledge of experts in the field.

The omega-3 fatty acids are known for their triglyceride-loweringeffects and for their effects in raising the levels of high-densitylipoproteins (HDL). These fatty acids can be obtained by synthesis or,preferably, from fish oil. In that case, it is possible to use variousmixtures of omega-3 fatty acids depending on their characteristics.Preferably, the omega-3 fatty acids are the long-chain ones (from 20 to22 carbon atoms). The ones most preferred are5,8,11,14,17-eicosapentanoic acid (EPA) and cis0,13,16,19-docosahexanoic acid (DHA). In a preferred embodiment of theinvention, the omega-5 fatty acid is cis 4,7,10,13,16,19-docosahexanoicacid (DHA), most preferably in a ratio of 1:1. These omega-3 fatty acidscan optionally be esterified or salified to pharmaceutically acceptablederivatives, with alcohols or bases, respectively. The omega-3 fattyacids, or their esters or salts, alone or in mixtures thereof, can beprocured on the market, or can be prepared by known methods. Themixtures can be specifically formulated for the combination according tothe invention.

Coenzyme Q10 is now so well known in its human use that it requires noparticular explanation and the substance is available on the market.Experts in the field can refer to the patent documents filed by thepresent applicant, where this substance is amply described.

Similar considerations also apply to resveratrol.

The policosanols are long-chain aliphatic alcohols. Examples ofpolicosanols are triacontanol, hexacosanol, hexacontanol, ecocontanol,tetra-cosanol, dotriacontanol, and tetracontanol. The policosonal can bepre-sent as such or in the form of an extract from natural products thatcontain it, e.g. wheat or rice germs, the waxy cuticle of sugar cane, orGinkgo biloba leaves. See, for example, WO 99/06039.

Pantethine is used on compositions for hair cosmetics and also incompositions for the treatment of dyslipidaemias, as described, forexample, in WO 2004/041257. It is therefore a well-known compoundavailable to the expert in the field.

Selenium and zinc are commonly used in food supplements, as described inseveral patents, e.g. EP 0 797 993 and U.S. Pat. No. 6,602,512.

As already mentioned, the individual components have long been used inhuman subjects, and therefore their pharmaco-toxicological profiles areknown.

This implies that, apart from the consideration of the synergisticeffect demonstrated here below, the dosages and ratios of the individualcomponents can be determined by the expert in the field with normalpreclinical and clinical trials, or with the usual considerationsregarding the formulation of a dietetic product.

The amounts of the individual compounds advised for the preparation of apharmaceutical composition for human use are the following.

Omega-3 fatty acid: from 500 mg to 2 g/day, preferably 1 g/day;

Simvastatin; from 10 mg to 40 mg/day, preferably 10 mg/day;

Coenzyme Q10: from 5 mg to 50 mg/day, preferably 10 mg/day;

Resveratrol: from 1 mg to 5 mg/day, preferably 2.5 mg/day;

Policosanols: hexacosanol: from 5 mg to 15 mg/day, preferably 10 mg/day;

Pantethine: from 10 mg to 30 mg/day, preferably 20 mg/day;

Selenium: from 25 μg to 75 μg/day, preferably 50 μg/day;

Zinc: from 5 mg to 15 mg/day, preferably 10 mg/day.

The pharmaceutical composition can have a unitary form, in which theactive ingredients are present in a single pharmaceutical form (tablet,sachet, capsule, vial) or the active ingredients can be administered ina coordinated sequential manner. In the latter case, the pharmaceuticalcomposition can be formulated, supplying the components in separatecontainers, accompanied by instructions for their sequentialadministration.

The compositions covered by the present invention are entirelyconventional and are obtained with methods that are common practice inthe pharmaceutical industry. According to the administration route optedfor, the compositions will be in solid or liquid form, suitable fororal, parenteral or intravenous administration. The compositionsaccording to the present invention contain, along with the activeingredient, at least one pharmaceutically acceptable vehicle orexcipient. Particularly useful may be formulation adjuvants such as, forexample, solubilising agents, dispersing agents, suspension agents andemulsifying agents. A general reference work is Remington'sPharmaceutical Sciences Handbook, latest edition.

The following examples further illustrate the invention.

EXAMPLE 1 Antidiabetic and Serum Lipid-Lowering Activity in db/db Mice

Mutations in laboratory animals have made it possible to develop modelsthat present non-insulin-dependent diabetes associated with obesity,hyperlipidaemia and insulin resistance and that enable us to test theefficacy of new antidiabetic compounds (Reed and Scribner, Diabetes,obesity and metabolism 1: 75-86, 1999).

A much used genetically diabetic mouse model is the C57BL/KsJ db/dbmouse.

The genetic basis of this model is a defect in the leptin receptor genewhich gives rise to leptin resistance and leads to hyperphagia, obesity,hyperinsulinaemia and insulin resistance, with subsequent symptoms ofinsufficient insulin secretion and hyperglycaemia (Kodama et al.,Diabetologia 37: 739-744, 1994; Chen et al., Cell 84: 491-495, 1996).Since hyperglycaemia is accompanied by obesity and insulin resistance,the db/db mouse has characteristics that are close to those of type 2diabetes in man and is useful for assaying insulin-sensitisingcompounds.

The C57BL/KsJ db/db mice used in the experiments were supplied byJackson Lab (via Ch. River). After 10 days of acclimatisation instandard conditions (22±2° C.; 55±15% humidity; 15-20 air changes/hour;12 hour light-darkness cycle with light from 7 a.m. to 7 p.m.) on astandard 4 RF21 diet (Mucedola), blood samples were taken inpost-absorption conditions (fasting from 8.30 a.m. to 4.30 p.m.) fromthe caudal vein with the aid of a Jelco 22G catheter (Johnson andJohnson). Glucose, insulin, triglyceride, cholesterol, free fatty acidand urea levels were checked in the plasma to ensure well-matcheddistribution of the mice in the treatment groups.

At the start of treatment, the body weight of the animals was checkedand monitoring of the animals' consumption of water and feed wasscheduled.

The mice were divided into groups and treated orally twice daily with:

Omega-3 fatty acid (EPA+DHA 1:1) 200 mg/kg;

Simvastatin 100 mg/kg;

Omega-3 fatty acid (200 mg/kg)+simvastatin (100 mg/kg);

Omega-3 fatty acid (200 mg/kg)+simvastatin (100 mg/kg); Coenzyme Q10 (50mg/kg)+resveratrol (5 mg/kg)+policosanols (hexacosanol 25mg/kg)+pantethine (100 mg/kg+selenium (0.5 μg/kg)+zinc (2.5 mg/kg).

In the course of the experiment, serum glucose levels, glucose tolerance(OGTT), a number of lipid status variables and weight gain weremonitored.

The combination according to the invention was capable of lowering serumglucose levels in the feeding condition (Table 1); in thepost-absorption condition (Table 2); and in the fasting condition (Table3); and capable of improving glucose tolerance (Table 4), and ofreducing the levels of fructosamine, an indicator of proteinglycosylation (Table 5) which, as mentioned above, plays an importantrole in the development of the micro- and macrovascular complications ofdiabetes.

The combination according to the invention also shows good ability toreduce serum triglyceride levels (Table 6) and to increaseHDL-cholesterol levels (Table 7).

An increase in HDL-cholesterol values constitutes an indicator of areduced risk of atherosclerosis and of cardiovascular complications suchas atherosclerosis and infarct. TABLE 1 P Glucose % Student's Compoundmg/dl Variation t-test) Control 487 ± 25 Simvastatin 450 ± 21 −7.6 NSOmega-3 466 ± 28 −4.3 NS Omega-S + simvastatin 403 ± 34 −17.2 NS Omega-3(200 mg/kg) + simvastatin 303 ± 16 −37.8 P < 0.001 (100 mg/kg) +Coenzyme Q10 vs control (50 mg/kg) + resveratrol (5 mg/kg) + hexacosanol25 mg/kg) + pantethine (100 mg/kg + selenium (0.5 μg/kg) + zinc (2.5mg/kg)Number of animals per group: 6.Blood glucose levels of db/db mice, treated orally twice daily for 12days with the compounds and at the doses indicated in the table. Samplein feeding condition, approximately 15 hours after the last treatment.Mean values ± S.E. and variation (%) vs control.

TABLE 2 P Glucose % Student's Compound mg/dl Variation t-test) Control414 ± 11 Simvastatin 419 ± 33 1.2 NS Omega-3 421 ± 30 1.6 NS Omega-3 +simvastatin 409 ± 11 −1.2 NS Omega-3 (200 mg/kg) + 216 ± 16 −47.8 P <0.001 simvastatin (100 mg/kg); + vs control Coenzyme Q10 (50 mg/kg) +res- veratrol (5 mg/kg) + hexacosanol 25 mg/kg) + pantethine (100mg/kg + selenium (0.5 □g/kg) + zinc (2.5 mg/kg)Number of animals per group: 6.Blood glucose levels of db/db mice, treated orally twice daily for 12days with the compounds and at the doses indicated in the table. Samplein post-absorption condition (fasting from 9 a.m. to 5 p.m.) and 8 hoursafter the last treatment.Mean values ± S.E. and variation (%) vs control.

TABLE 3 P Glucose % Student's Compound mg/dl Variation t-test) Control344 ± 35 Simvastatin 325 ± 27 −5.5 NS Omega-3 314 ± 21 −8.7 NS Omega-3 +simvastatin 384 ± 20 11.6 NS Omega-3 (200 mg/kg) + simvastatin 144 ± 3 −58.0 P < 0.001 (100 mg/kg); + Coenzyme Q10 vs control (50 mg/kg) +resveratrol (5 mg/kg) + hexacosanol 25 mg/kg) + pantethine (100 mg/kg +selenium (0.5 μg/kg) + zinc (2.5 mg/kg)Number of animals per group: 6.Blood glucose levels of db/db mice, treated orally twice daily for 18days with the compounds and at the doses indicated in the table. Samplein mice fasted for 18 hours and 5 hours after the last treatment.Mean values ± S.E. and variation (%) vs control.

TABLE 4 P AUC Glucose % Student's Compound u.a. Variation t-test Control51182 ± 2392 Simvastatin 48174 ± 3555 −5.9 NS Omega-3 46476 ± 1827 −9.2NS Omega-3 + simvastatin 45192 ± 1546 −11.7 NS Omega-3 (200 mg/kg) +24527 ± 889  −52.1 P < 0.001 simvastatin (100 mg/kg); + vs controlCoenzyme Q10 (50 mg/kg) + resveratrol (5 mg/kg) + hexacosanol 25mg/kg) + pantethine (100 mg/kg + selenium (0.5 μg/kg) + zinc (2.5 mg/kg)Number of animals: 6.Area under the curve (AUC) of the OGTT in the blood of db/db mice,treated orally twice daily for 18 days with the compounds and at thedoses indicated in the table. OGTT test (glucose 3 g/kg) in mice fastedfor 18 hours and 5 hours after the last treatment.Mean values ± S.E. and variation (%) vs control.

TABLE 5 P Fructosamine % Student's Compund mM Variation t-test Control0.80 ± 0.03 Simvastatin 0.78 ± 0.12 −2.5 NS Omega-3 0.81 ± 0.04 1.3 NSOmega-3 + simvastatin 0.82 ± 0.02 2.5 NS Omega-3 (200 mg/kg) + sim- 0.41± 0.04 −48.8 P < 0.001 vastatin (100 mg/kg) + vs control Coenzyme Q10(50 mg/kg) + resveratrol (5 mg/kg) + hex- acosanol 25 mg/kg) +pantethine (100 mg/kg + selenium (0.5 μg/kg) + zinc (2.5 mg/kg)Number of animals per group: 6.Plasma fructosamine levels of db/db mice, treated orally twice daily for25 days with the compounds and at the doses indicated in the table.Sample in post-absorption condition (fasting from 9 a.m. to 4.30 p.m.)and 7.30 hours after the last treatment.Mean values ± S.E. and variation (%) vs control.

TABLE 6 Triglycer- P ides Student's Compound mg/dl Variation t-testControl 95.4 ± 6.2 Simvastatin 79.7 ± 5.1 −16.5 NS Omega-3  88.3 ± 10.7−7.4 NS Omega-3 + simvastatin 73.5 ± 4.5 −22.9 0.05  vs control Omega-3(200 mg/kg) + 45.3 ± 2.3 −52.5 0.001 simvastatin (100 mg/kg) + vscontrol Coenzyme Q10 (50 mg/kg) + resveratrol (5 mg/kg) + hexacosanol 25mg/kg) + pantethine (100 mg/kg + selenium (0.5 μg/kg) + zinc (2.5 mg/kg)Number of animals per group: 6.Plasma triglyceride levels of db/db mice, treated orally twice daily for25 days with the compounds and at the doses indicated in the table.Sample in post-absorption condition (fasting from 9 a.m. to 4.30 p.m.)and 7.30 hours after the last treatment.Mean values ± S.E. and variation (%) vs control.

TABLE 7 HDL- P cholesterol % Student's Compound mg/dl Variation t-testControl 82.0 ± 5.1 Simvastatin 72.4 ± 4.6 −11.7 NS Omega-3 74.8 ± 3.8−8.8 NS Omega-3 + simva-statin 78.4 ± 4.1 −4.4 NS Omega-3 (200 mg/kg) +simvastatin 98.0 ± 3.5 19.5 0.05 (100 mg/kg); + Coenzyme Q10 vs control(50 mg/kg) + resveratrol (5 mg/kg) + hexacosanol 25 mg/kg) + pantethine(100 mg/kg + selenium (0.5 μg/kg) + zinc (2.5 mg/kg)Plasma HDL-cholesterol levels of db/db mice, treated orally twice dailyfor 25 days with the compounds and at the doses indicated in the table.Sample in post-absorption conditions (fasting from 9 a.m. to 4.30 p.m.)and 7.30 hours after the last treatment.Mean values ± S.E. and variation (%) vs control.

The results reported above clearly demonstrate the unexpected synergismof the combination according to the present invention, contrary to whatwas expected on the basis of the individual components, or even of thecombination of simvastatin and omega-3 fatty acids.

1. Combination consisting essentially of at least one omega-3 fattyacid, optionally esterified or salified, at least one statin, CoenzymeQ10, resveratrol, at least one policosanol, pantethine, selenium, andzinc.
 2. Combination according to claim 1, in which the statin isselected from the group consisting of simvastatin, lovastatin,fluvastatin, pravastatin, atorvastatin, cerivastatin and rosuvastatin.3. Combination according to claim, in which the omega-3 fatty acids arelong-chain.
 4. Combination according to claim 1, in which the omega-3fatty acid is selected from the group consisting of cis5,8,11,14,17-eicosapentanoic acid (EPA) and cis4,7,10,13,16,19-docosahexanoic acid (DHA), one of their esters orpharmaceutically acceptable salts.
 5. Combination according to claim 4,in which the cis 5,8,11,14,17-eicosapentanoic acid and the cis4,7,10,13,16,19-docosahexanoic acid (DHA), one of their esters orpharmaceutically acceptable salts are in a ratio of 1:1.
 6. Combinationaccording to claim 1, in which the policosanol is selected from thegroup consisting of triacontanol, hexacosanol, hexacontanol,ecocontanol, tetracosanol, dotriacontanol, and tetracontanol. 7.Combination according to claim 6, in which the policosanol is present assuch or in the form of an extract from natural products that contain it.8. Combination according to claim 7, in which the natural product isselected from the group consisting of wheat or rice germs, the waxycuticle of sugar cane, and Ginkgo biloba leaves.
 9. Pharmaceuticalcomposition containing the combination according to claim 1, optionallyin a mixture with at least one pharmaceutically acceptable vehicle orexcipient.
 10. Pharmaceutical composition according to claim 9, suitablefor the administration of the following dosages: a. omega-3 fatty acid:from 500 mg to 2 g/day; b. simvastatin: from 10 mg to 40 mg/day; c.Coenzyme Q10: from 5 mg to 50 mg/day; d. resveratrol: from 1 mg to 5mg/day; e. policosanols: hexacosanol: from 5 mg to 15 mg/day; f.pantethine: from 10 mg to 30 mg/day; g. selenium: from 25 μg to 75μg/day; h. zinc: from 5 mg to 15 mg/day.
 11. Pharmaceutical compositionaccording to claim, suitable for the administration in unitary form, orin coordinated, sequential form, of the components of the combination.12. Food supplement containing the combination according to claim 1,optionally in a mixture with at least one acceptable vehicle orexcipient for human or animal use. 13-19. (canceled)
 20. A method forthe treatment of type 2 diabetes and insulin resistance, comprisingadministering to a subject in need thereof a combination consistingessentially of at least one omega-3 fatty acid, optionally esterified orsalified, at least one statin, Coenzyme Q10, resveratrol, at least onepolicosanol, pantethine, selenium, and zinc.
 21. The method according toclaim 20, in which the statin is selected from the group consisting ofsimvastatin, lovastatin, fluvastatin, pravastatin, atorvastatin,cerivastatin and rosuvastatin.
 22. The method according to claim 20, inwhich the omega-3 fatty acids are long-chain.
 23. The method accordingto claim 22, in which the omega-3 fatty acid is selected from the groupconsisting of cis 5,8,11,14,17-eicosapentanoic acid (EPA) and cis4,7,10,13,16,19-docosahexanoic acid (DHA), one of their esters orpharmaceutically acceptable salts.
 24. The method according to claim 23,in which the cis 5,8,11,14,17-eicosapentanoic acid and the cis4,7,10,13,16,19-docosahexanoic acid (DHA), one of their esters orpharmaceutically acceptable salts are in a ratio of 1:1.
 25. The methodaccording to claim 20, in which the policosanol is selected from thegroup consisting of triacontanol, hexacosanol, hexac-ontanol,ecocontanol, tetracosanol, dotriacontanol, and tetracontanol.
 26. Themethod according to claim 25, in which the policosanol is present assuch or in the form of an extract from natural products that contain it.27. The method according to claim 26, in which the natural product isselected from the group consisting of wheat or rice germs, the waxycuticle of sugar cane, and Ginkgo biloba leaves.
 28. The methodaccording to claim 20, in which said combination is optionally in amixture with at least one pharmaceutically acceptable vehicle orexcipient.
 29. The method according to claim 28, in which saidcombination is suitable for the administration of the following dosages:a. omega-3 fatty acid: from 500 mg to 2 g/day; b. simvastatin: from 10mg to 40 mg/day; c. Coenzyme Q10 from 5 mg to 50 mg/day; d. resveratrol:from 1 mg to 5 mg/day; e. policosanols: hexacosanol: from 5 mg to 15mg/day; f. pantethine: from 10 mg to 30 mg/day; g. selenium: from 25 μgto 75 μg/day; h. zinc: from 5 mg to 15 mg/day.
 30. The method accordingto claim 20, in which the components of said combination areadministered in unitary form, or in coordinated, sequential form. 31.The method according to claim 20, in which said combination isadministered in the form of a pharmaceutical composition or a foodsupplement.
 32. A method for the treatment of subject in need ofantilipaemic action, comprising administering to said subject acombination consisting essentially of at least one omega-3 fatty acid,optionally esterified or salified, at least one statin, Coenzyme Q10,resveratrol, at least one policosanol, pantethine, selenium, and zinc.33. The method according to claim 32, in which the statin is selectedfrom the group consisting of simvastatin, lovastatin, fluvastatin,pravastatin, atorvastatin, cerivastatin and rosuvastatin.
 34. The methodaccording to claim 32, in which the omega-3 fatty acids are long-chain.35. The method according to claim 33, in which the omega-3 fatty acid isselected from the group consisting of cis 5,8,11,14,17-eicosapentanoicacid (EPA) and cis 4,7,10,13,16,19-docosahexanoic acid (DHA), one oftheir esters or pharmaceutically acceptable salts.
 36. The methodaccording to claim 35, in which the cis 5,8,11,14,17-eicosapentanoicacid and the cis 4,7,10,13,16,19-docosahexanoic acid (DHA), one of theiresters or pharmaceutically acceptable salts are in a ratio of 1:1. 37.The method according to claim 32, in which the policosanol is selectedfrom the group consisting of triacontanol, hexacosanol, hexac-ontanol,ecocontanol, tetracosanol, dotriacontanol, and tetracontanol.
 38. Themethod according to claim 37, in which the policosanol is present assuch or in the form of an extract from natural products that contain it.39. The method according to claim 38, in which the natural product isselected from the group consisting of wheat or rice germs, the waxycuticle of sugar cane, and Ginkgo biloba leaves.
 40. The methodaccording to claim 32, in which said combination is optionally in amixture with at least one pharmaceutically acceptable vehicle orexcipient.
 41. The method according to claim 32, in which saidcombination is suitable for the administration of the following dosages:a. omega-3 fatty acid: from 500 mg to 2 g/day; b. simvastatin: from 10mg to 40 mg/day; c. Coenzyme Q10: from 5 mg to 50 mg/day; d.resveratrol: from 1 mg to 5 mg/day; e. policosanols: hexacosanol: from 5mg to 15 mg/day; f. pantethine: from 10 mg to 30 mg/day; g. selenium:from 25 μg to 75 μg/day; h. zinc: from 5 mg to 15 mg/day.
 42. The methodaccording to claim 32, in which the components of said combination areadministered in unitary form, or in coordinated, sequential form. 43.The method according to claim 32, in which said combination isadministered in the form of a pharmaceutical composition or a foodsupplement.
 44. A method for the treatment of a subject in need of aprotective action on the cardio-vascular system, comprisingadministering to said subject a combination consisting essentially of atleast one omega-3 fatty acid, optionally esterified or salified, atleast one statin, Coenzyme Q10, resveratrol, at least one policosanol,pantethine, selenium, and zinc.
 45. The method according to claim 44, inwhich the statin is selected from the group consisting of simvastatin,lovastatin, fluvastatin, pravastatin, atorvastatin, cerivastatin androsuvastatin.
 46. The method according to claim 44, in which the omega-3fatty acids are long-chain.
 47. The method according to claim 46, inwhich the omega-3 fatty acid is selected from the group consisting ofcis 5,8,11,14,17-eicosapentanoic acid (EPA) and cis4,7,10,13,16,19-docosahexanoic acid (DHA), one of their esters orpharmaceutically acceptable salts.
 48. The method according to claim 47,in which the cis 5,8,11,14,17-eicosapentanoic acid and the cis4,7,10,13,16,19-docosahexanoic acid (DHA), one of their esters orpharmaceutically acceptable salts are in a ratio of 1:1.
 49. The methodaccording to claim 44, in which the policosanol is selected from thegroup consisting of triacontanol, hexacosanol, hexac-ontanol,ecocontanol, tetracosanol, dotriacontanol, and tetracontanol.
 50. Themethod according to claim 49, in which the policosanol is present assuch or in the form of an extract from natural products that contain it.51. The method according to claim 50, in which the natural product isselected from the group consisting of wheat or rice germs, the waxycuticle of sugar cane, and Ginkgo biloba leaves.
 52. The methodaccording to claim 44, in which said combination is optionally in amixture with at least one pharmaceutically acceptable vehicle orexcipient.
 53. The method according to claim 52, in which saidcombination is suitable for the administration of the following dosages:a. omega-3 fatty acid: from 500 mg to 2 g/day; b. simvastatin: from 10mg to 40 mg/day; c. Coenzyme Q10: from 5 mg to 50 mg/day; d.resveratrol: from 1 mg to 5 mg/day; e. policosanols: hexacosanol: from 5mg to 15 mg/day; f. pantethine: from 10 mg to 30 mg/day; g. selenium:from 25 μg to 75 μg/day; h. zinc: from 5 mg to 15 mg/day.
 54. The methodaccording to claim 44, in which the components of said combination areadministered in unitary form, or in coordinated, sequential form. 55.The method according to claim 44, in which said combination isadministered in the form of a pharmaceutical composition or a foodsupplement.
 56. A method for the treatment of diseases involving insulinresistance, comprising administering to a subject in need thereof acombination consisting essentially of at least one omega-3 fatty acid,optionally esterified or salified, at least one statin, Coenzyme Q10,resveratrol, at least one policosanol, pantethine, selenium, and zinc.57. The method according to claim 56, in which the statin is selectedfrom the group consisting of simvastatin, lovastatin, fluvastatin,pravastatin, atorvastatin, cerivastatin and rosuvastatin.
 58. The methodaccording to claim 56, in which the omega-3 fatty acids are long-chain.59. The method according to claim 58, in which the omega-3 fatty acid isselected from the group consisting of cis 5,8,11,14,17-eicosapentanoicacid (EPA) and cis 4,7,10,13,16,19-docosahexanoic acid (DHA), one oftheir esters or pharmaceutically acceptable salts.
 60. The methodaccording to claim 59, in which the cis 5,8,11,14,17-eicosapentanoicacid and the cis 4,7,10,13,16,19-docosahexanoic acid (DHA), one of theiresters or pharmaceutically acceptable salts are in a ratio of 1:1. 61.The method according to claim 56, in which the policosanol is selectedfrom the group consisting of triacontanol, hexacosanol, hexac-ontanol,ecocontanol, tetracosanol, dotriacontanol, and tetracontanol.
 62. Themethod according to claim 61, in which the policosanol is present assuch or in the form of an extract from natural products that contain it.63. The method according to claim 62, in which the natural product isselected from the group consisting of wheat or rice germs, the waxycuticle of sugar cane, and Ginkgo biloba leaves.
 64. The methodaccording to claim 56, in which said combination is optionally in amixture with at least one pharmaceutically acceptable vehicle orexcipient.
 65. The method according to claim 64, in which saidcombination is suitable for the administration of the following dosages:a. omega-3 fatty acid: from 500 mg to 2 g/day; b. simvastatin: from 10mg to 40 mg/day; c. Coenzyme Q10: from 5 mg to 50 mg/day; d.resveratrol: from 1 mg to 5 mg/day; e. policosanols: hexacosanol: from 5mg to 15 mg/day; f. pantethine: from 10 mg to 30 mg/day; g. selenium:from 25 μg to 75 μg/day; h. zinc: from 5 mg to 15 mg/day.
 66. The methodaccording to claim 56, in which the components of said combination areadministered in unitary form, or in coordinated, sequential form. 67.The method according to claim 56, in which said combination isadministered in the form of a pharmaceutical composition or a foodsupplement.
 68. The method according to claim 56, in which said diseaseis selected from the group consisting of type 2 diabetes and itscomplications, syndrome X, polycystic ovary syndrome, obesity,hypertension, hyperlipidaemias and hypercholesterolaemias.
 69. A methodfor the combined treatment of type 2 diabetes and insulin resistance,and exerting antilipaemic action and protective action on thecardiovascular system, comprising administering to a subject in needthereof a combination consisting essentially of at least one omega-3fatty acid, optionally esterified or salified, at least one statin,Coenzyme Q10, resveratrol, at least one policosanol, pantethine,selenium, and zinc.
 70. The method according to claim 69, in which thestatin is selected from the group consisting of simvastatin, lovastatin,fluvastatin, pravastatin, atorvastatin, cerivastatin and rosuvastatin.71. The method according to claim 69, in which the omega-3 fatty acidsare long-chain.
 72. The method according to claim 71, in which theomega-3 fatty acid is selected from the group consisting of cis5,8,11,14,17-eicosapentanoic acid (EPA) and cis 4,7,10,13,16,19-docosahexanoic acid (DHA), one of their esters or pharmaceuticallyacceptable salts.
 73. The method according to claim 72, in which the cis5,8,11,14,17-eicosapentanoic acid and the cis4,7,10,13,16,19-docosahexanoic acid (DHA), one of their esters orpharmaceutically acceptable salts are in a ratio of 1:1.
 74. The methodaccording to claim 69, in which the policosanol is selected from thegroup consisting of triacontanol, hexacosanol, hexac-ontanol,ecocontanol, tetracosanol, dotriacontanol, and tetracontanol.
 75. Themethod according to claim 74, in which the policosanol is present assuch or in the form of an extract from natural products that contain it.76. The method according to claim 75, in which the natural product isselected from the group consisting of wheat or rice germs, the waxycuticle of sugar cane, and Ginkgo biloba leaves.
 77. The methodaccording to claim 69, in which said combination is optionally in amixture with at least one pharmaceutically acceptable vehicle orexcipient.
 78. The method according to claim 77, in which saidcombination is suitable for the administration of the following dosages:a. omega-3 fatty acid: from 500 mg to 2 g/day; b. simvastatin: from 10mg to 40 mg/day; c. Coenzyme Q10: from 5 mg to 50 mg/day; d.resveratrol: from 1 mg to 5 mg/day; e. policosanols: hexacosanol: from 5mg to 15 mg/day; f. pantethine: from 10 mg to 30 mg/day; g. selenium:from 25 μg to 75 μg/day; h. zinc: from 5 mg to 15 mg/day.
 79. The methodaccording to claim 69, in which the components of said combination areadministered in unitary form, or in coordinated, sequential form. 80.The method according to claim 69, in which said combination isadministered in the form of a pharmaceutical composition or a foodsupplement.
 81. The method according to claim 69, in which said diseaseis selected from the group consisting of type 2 diabetes and itscomplications, syndrome X, polycystic ovary syndrome, obesity,hypertension, hyperlipidaemias and hypercholesterolaemias.